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Gene silencing through RNA interference: Potential for therapeutics and functional genomics

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Abstract

A major focus of biology is determining the role that specific genes play within a cell. The ability to control gene expression is a powerful tool for biologists, and methods that facilitate the expression of genes in trans have been very useful in delineating gene function. However, methods that enable researchers to decease or inhibit gene expression in a controlled and specific manner have been lacking. A significant advancement in the field of gene silencing is the recent discovery of RNA interference (RNAi), a post-transcriptional gene silencing mechanism first described in C. elegansand Drosophilaand more recently shown to occur in mammals, including mouse and human cells. This chapter will examine several aspects of RNAi and its related gene silencing mechanisms and will discuss the impact that technologies based on these endogenous cellular processes have had on studies of gene function and on new approaches to the treatment of disease.

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References

  1. Napoli, C., Lemieux, C. and Jorgensen, R., Introduction of a chimeric chalcone synthase gene into petunia results in reversible co-suppression of homologous genes in trans. Plant Cell 2(4) (1990) 279.

    Article  CAS  PubMed  Google Scholar 

  2. Van der Krol, A.R., Mur, L.A., Beld, M. et al.,Flavonoid genes in petunia: Addition of a limited number of gene copies may lead to a suppression of gene expression. Plant Cell 2(4) (1990) 291.

    Article  CAS  PubMed  Google Scholar 

  3. Romano, N. and Macino, G., Quelling: Transient inactivation of gene expression in Neurospora crassaby transformation with homologous sequences. Mol. Microbiol., 6(22) (1992) 3343.

    CAS  PubMed  Google Scholar 

  4. Vaucheret, H., Beclin, C. and Fagard, M., Posttranscriptional gene silencing in plants. J. Cell Sci. 114(Pt17) (2001) 3083.

    CAS  PubMed  Google Scholar 

  5. Fire, A., Xu, S., Montgomery, M.K. et al.,Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391(6669) (1998) 806.

    Article  CAS  PubMed  Google Scholar 

  6. Kennerdell, J.R. and Carthew, R.W., Use of dsRNA-mediated genetic interference to demonstrate that frizzledand frizzled 2act in the wingless pathway. Cell 95(7) (1998) 1017.

    Article  CAS  PubMed  Google Scholar 

  7. Misquitta, L. and Paterson, B.M., Targeted disruption of gene function in Drosophilaby RNA interference (RNA-i): A role for nautilusin embryonic somatic muscle formation. Proc. Natl. Acad. Sci. USA 96(4) (1999) 1451.

    Article  CAS  PubMed  Google Scholar 

  8. Hamilton, A.J. and Baulcombe, D.C., A species of small antisense RNA in posttranscriptional gene silencing in plants. Science, 286(5441) (1999) 950.

    Article  CAS  PubMed  Google Scholar 

  9. Hammond, S.M., Bernstein, E., Beach, D. et al.,An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophilacells. Nature 404(6775) (2001) 293.

    Google Scholar 

  10. Zamore, P.D., Tuschl, T., Sharp, P.A. et al.,RNAi: Doublestranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101(1) (2000) 25.

    Article  CAS  PubMed  Google Scholar 

  11. Yang, D., Lu, H. and Erickson, J.W., Evidence that processed small dsRNAs may mediate sequence-specific mRNA degradation during RNAi in Drosophilaembryos. Curr. Biol., 10(19) (2002) 1191.

    Google Scholar 

  12. Elbashir, S.M., Lendeckel, W. and Tuschl, T., RNA interference is mediated by 21-and 22-nucleotide RNAs. Genes Dev., 15(2) (2001) 188.

    Article  CAS  PubMed  Google Scholar 

  13. Elbashir, S.M., Martinez, J., Patkaniowska, A. et al.,Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogasterembryo lysate. Embo J., 20(23) (2001) 6877.

    Article  CAS  PubMed  Google Scholar 

  14. Cogoni, C., Homology-dependent gene silencing mechanisms in fungi. Annu. Rev. Microbiol. 55 (2001) 381.

    Article  CAS  PubMed  Google Scholar 

  15. Parrish, S., Fleenor, J., Xu, S. et al.,Functional anatomy of a dsRNA trigger. Differential requirement for the two trigger strands in RNA interference. Mol. Cell 6(5) (2000) 1077.

    Article  CAS  PubMed  Google Scholar 

  16. Bernstein, E., Caudy, A.A., Hammond, S.M. et al.,Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409(6818) (2001) 363.

    Google Scholar 

  17. Cerutti, L., Mian, N. and Bateman, A., Domains in gene silencing and cell differentiation proteins: the novel PAZ domain and redefinition of the Piwi domain. Trends Biochem. Sci. 25 (2000) 481.

    Article  CAS  PubMed  Google Scholar 

  18. Nykanen, A., Haley, B. and Zamore, P.D., ATP requirements and small interfering RNA structure in the RNA interference pathway. Cell, 107(3) (2001) 309.

    Article  CAS  PubMed  Google Scholar 

  19. Martinez, J., Patkaniowska, A., Urlaub, H. et al.,Singlestranded antisense siRNAs guide target RNA cleavage in RNAi. Cell, 110(5) (2002) 563.

    Article  CAS  PubMed  Google Scholar 

  20. Schwarz, D.S., Hutvagner, G., Haley, B. et al.,Evidence that siRNAs function as guides, not primers, in the Drosophilaand human RNAi pathways. Mol. Cell, 10(3) (2002) 537.

    Article  CAS  PubMed  Google Scholar 

  21. Hammond, S.M., Boettcher, S., Caudy, A.A. et al.,Argonaute2, a link between genetic and biochemical analyses of RNAi. Science, 293(5532) (2001) 1146.

    Article  CAS  PubMed  Google Scholar 

  22. Caudy, A.A., Myers, M., Hannon, G.J. et al.,Fragile Xrelated protein and VIG associate with the RNA interference machinery. Genes Dev., 16(19) (2002) 2491.

    Article  CAS  PubMed  Google Scholar 

  23. Ishizuka, A., Siomi, M.C., Siomi, H., A Drosophilafragile X protein interacts with components of RNAi and ribosomal proteins. Genes Dev., 16(19) (2002) 2497.

    Article  CAS  PubMed  Google Scholar 

  24. Cogoni, C., Irelan, J.T., Schumacher, M. et al.,Transgene silencing of the al-1 gene in vegetative cells of Neurospora is mediated by a cytoplasmic effector and does not depend on DNA-DNA interactions or DNA methylation. Embo J., 15(12) (1996) 3153.

    CAS  PubMed  Google Scholar 

  25. Palauqui, J.C., Elmayan, T., Pollien, J.M. et al.,Systemic acquired silencing: transgene-specific post-transcriptional silencing is transmitted by grafting from silenced stocks to non-silenced scions. Embo J., 16(15) (1997) 4738.

    Article  CAS  PubMed  Google Scholar 

  26. Montgomery, M.K., Xu, S. and Fire, A., RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA, 95(26) (1998) 15502.

    Article  CAS  PubMed  Google Scholar 

  27. Cogoni, C. and Macino, G., Gene silencing in Neurospora crassarequires a protein homologous to RNA-dependent RNA polymerase. Nature, 399(6732) (1999) 166.

    CAS  PubMed  Google Scholar 

  28. Smardon, A., Spoerke, J.M., Stacey, S.C. et al.,EGO-1 is related to RNA-directed RNA polymerase and functions in germ-line development and RNA interference in C.elegans[published erratum appears in Curr. Biol.], 2000, 18 May;10(10):R393-4]. Curr. Biol., 10(4) (2000) 169.

    Article  CAS  PubMed  Google Scholar 

  29. Sijen, T., Fleenor, J., Simmer, F. et al.,On the role of RNA amplification in dsRNA-triggered gene silencing. Cell, 107(4) (2001) 465.

    Article  CAS  PubMed  Google Scholar 

  30. Makeyev, E.V. and Bamford, D.H., Cellular RNA-dependent RNA polymerase involved in posttranscriptional gene silencing has two distinct activity modes. Mol. Cell, 10(6) (2002) 1417.

    Article  CAS  PubMed  Google Scholar 

  31. Alder, M.N., Dames, S., Gaudet, J. et al.,Gene silencing in Caenorhabditis elegansby transitive RNA interference. Rna 9(1) (2003) 25.

    Article  CAS  PubMed  Google Scholar 

  32. Vance, V. and Vaucheret, H., RNA silencing in plantsdefense and counterdefense. Science, 292(5525) (2001) 2277.

    Article  CAS  PubMed  Google Scholar 

  33. Li, W.X. and Ding, S.W., Viral suppressors of RNA silencing. Curr. Opin. Biotechnol., 12(2) (2001) 150.

    Article  CAS  PubMed  Google Scholar 

  34. Ahlquist, P., RNA-dependent RNA polymerases, viruses, and RNA silencing. Science, 296(5571) (2002) 1270.

    Article  CAS  PubMed  Google Scholar 

  35. Tabara, H., Sarkissian, M., Kelly, W.G. et al.,The rde-1gene, RNA interference, and transposon silencing in C.elegans. Cell, 99(2) (1999) 123.

    Article  CAS  PubMed  Google Scholar 

  36. Ketting, R.F., Haverkamp, T.H., Van Luenen, H.G. et al., Mut-7of C.elegans, required for transposon silencing and RNA interference, is a homolog ofWerner syndrome helicase and RNaseD. Cell, 99(2) (1999) 133.

    Article  CAS  PubMed  Google Scholar 

  37. Dennis, C., The brave new world of RNA. Nature, 418(6894) (2002) 122.

    Article  CAS  PubMed  Google Scholar 

  38. Hannon, G.J., RNA interference. Nature, 418(6894) (2002) 244.

    Article  CAS  PubMed  Google Scholar 

  39. McManus, M.T. and Sharp, P.A., Gene silencing in mammals by small interfering RNAs. Nat. Rev. Genet., 3(10) (2002) 737.

    Article  CAS  PubMed  Google Scholar 

  40. Volpe, T.A., Kidner, C., Hall, I.M. et al.,Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science, 297(5588) (2002) 1833.

    Article  CAS  PubMed  Google Scholar 

  41. Reinhart, B.J. and Bartel, D.P., Small RNAs correspond to centromere heterochromatic repeats. Science, 297(5588) (2002) 1831.

    Article  CAS  PubMed  Google Scholar 

  42. Hall, I.M., Shankaranarayana, G.D., Noma, K. et al.,Establishment and maintenance of a heterochromatin domain. Science, 297(5590) (2002) 2232.

    Article  CAS  PubMed  Google Scholar 

  43. Hall, I.M., Noma, K. and Grewal, S.I., RNA interference machinery regulates chromosome dynamics during mitosis and meiosis in fission yeast. Proc. Natl. Acad. Sci. USA 100(1) (2003) 193.

    Article  CAS  PubMed  Google Scholar 

  44. Zilberman, D., Cao, X., Jacobsen, S.E., ARGONAUTE4 control of locus-specific siRNA accumulation and DNA and histone methylation. Science, 299(5607) (2003) 716.

    Article  CAS  PubMed  Google Scholar 

  45. Lee, R.C., Feinbaum, R.L. and Ambros, V., The C.elegansheterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell, 75(5) (1993) 843.

    Article  CAS  PubMed  Google Scholar 

  46. Pasquinelli, A.E., Reinhart, B.J., Slack, F. et al.,Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature, 408(6808) (2000) 86.

    CAS  PubMed  Google Scholar 

  47. Lee, Y., Jeon, K., Lee, J.T. et al.,MicroRNA maturation: Stepwise processing and subcellular localization. Embo J., 21(17) (2002) 4663.

    Article  CAS  PubMed  Google Scholar 

  48. Grishok, A., Pasquinelli, A.E., Conte, D. et al.,Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C.elegansdevelopmental timing. Cell, 106(1) (2001) 23.

    Article  CAS  PubMed  Google Scholar 

  49. Hutvagner, G., McLachlan, J., Pasquinelli, A.E. et al.,A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science, 293(5531) (2001) 834.

    Article  CAS  PubMed  Google Scholar 

  50. Ketting, R.F., Fischer, S.E., Bernstein, E. et al.,Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C.elegans. Genes Dev., 15(20) (2001) 2654.

    Article  CAS  PubMed  Google Scholar 

  51. Knight, S.W. and Bass, B.L., A role for the RNase III enzyme DCR-1 in RNA interference and germ line development in Caenorhabditis elegans. Science, 293(5538) (2001) 2269.

    Article  CAS  PubMed  Google Scholar 

  52. Wightman, B., Ha, I. and Ruvkun, G., Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C.elegans. Cell, 75(5) (1993) 855.

    Article  CAS  PubMed  Google Scholar 

  53. Ha. I., Wightman, B. and Ruvkun, G., A bulged lin-4/lin-14 RNA duplex is sufficient for Caenorhabditis elegans lin-14 temporal gradient formation. Genes Dev., 10(23) (1996) 3041.

    CAS  PubMed  Google Scholar 

  54. Reinhart, B.J., Slack, F.J., Basson, M. et al.,The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature, 403(6772) (2000) 901.

    CAS  PubMed  Google Scholar 

  55. Lai, E.C., Micro RNAs are complementary to 3_ UTR sequence motifs that mediate negative post-transcriptional regulation. Nat. Genet., 30(4) (2002) 363.

    Article  CAS  PubMed  Google Scholar 

  56. Lagos-Quintana, M., Rauhut, R., Lendeckel, W. et al.,Identification of novel genes coding for small expressed RNAs. Science, 294(5543) (2001) 853.

    Google Scholar 

  57. Lau, N.C., Lim, L.P., Weinstein, E.G. et al.,An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science, 294(5543) (2001) 858.

    Article  CAS  PubMed  Google Scholar 

  58. Lee, R.C. and Ambros, V., An extensive class of small RNAs in Caenorhabditis elegans. Science, 294(5543) (2001) 862.

    Article  CAS  PubMed  Google Scholar 

  59. Reinhart, B.J., Weinstein, E.G., Rhoades, M.W. et al., MicroRNAs in plants. Genes Dev., 16(13) (2002) 1616.

    Article  CAS  PubMed  Google Scholar 

  60. Lagos-Quintana, M., Rauhut, R., Yalcin, A., et al.,Identification of tissue-specific microRNAs from mouse. Curr. Biol., 12(9) (2002) 735.

    CAS  PubMed  Google Scholar 

  61. Mourelatos, Z., Dostie, J., Paushkin, S. et al.,miRNPs: A novel class of ribonucleoproteins containing numerous microRNAs. Genes Dev., 16(6) (2002) 720.

    Article  CAS  PubMed  Google Scholar 

  62. Llave, C., Xie, Z., Kasschau, K.D. et al.,Cleavage of Scarecrow-like mRNA targets directed by a class of Arabidopsis miRNA. Science, 297(5589) (2002) 2053.

    Article  CAS  PubMed  Google Scholar 

  63. Lagos-Quintana, M., Rauhut, R., Meyer, J. et al.,New microRNAs from mouse and human. Rna 9(2) (2003) 175.

    Article  CAS  PubMed  Google Scholar 

  64. Dostie, J., Mourelatos, Z., Yang, M., et al.,Numerous microRNPs in neuronal cells containing novel microRNAs. Rna 9(2) (2003) 180.

    Article  CAS  PubMed  Google Scholar 

  65. Lim, L.P., Lau, N.C.,Weinstein, E.G. et al.,The microRNAs of Caenorhabditis elegans. Genes Dev., 17(8) (2003) 991.

    Article  CAS  PubMed  Google Scholar 

  66. Lim, L.P., Glasner, M.E., Yekta, S. et al.,Vertebrate microRNA genes. Science, 299(5612) (2003) 1540.

    Article  CAS  PubMed  Google Scholar 

  67. Ambros, V., Bartel, B., Bartel, D.P. et al.,A uniform system for microRNA annotation. Rna 9(3) (2003) 277.

    Article  CAS  PubMed  Google Scholar 

  68. Rhoades, M.W., Reinhart, B.J., Lim, L.P. et al.,Prediction of plant microRNA targets. Cell, 110(4) (2002) 513.

    Article  CAS  PubMed  Google Scholar 

  69. Brennecke, J. Hipfner, D.R. Stark, A. et al.,Bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell, 113(1) (2003) 25.

    Article  CAS  PubMed  Google Scholar 

  70. Xu, P., Vernooy, S.Y., Guo, M. et al.,The DrosophilaMicroRNA Mir-14 suppresses cell death and is required for normal fat metabolism. Curr. Biol., 13(9) (2003) 790.

    Article  CAS  PubMed  Google Scholar 

  71. Sempere, L.F., Sokol, N.S., Dubrovsky, E.B. et al.,Temporal regulation of microRNA expression in Drosophila melanogastermediated by hormonal signals and broad-Complex gene activity. Dev. Biol., 259(1) (2003) 9.

    Article  CAS  PubMed  Google Scholar 

  72. Calin, G.A., Dumitru, C.D., Shimizu, M. et al.,Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. USA, 99(24) (2002) 15524.

    Article  CAS  PubMed  Google Scholar 

  73. Seitz, H., Youngson, N., Lin, S.P. et al.,Imprinted microRNA genes transcribed antisense to a reciprocally imprinted retrotransposon-like gene. Nat. Genet. (2003).

  74. Clemens, M.J. and Elia, A., The double-stranded RNAdependent protein kinase PKR: Structure and function. J. Interferon Cytokine Res., 17(9) (1997) 503.

    CAS  PubMed  Google Scholar 

  75. Minks, M.A., West, D.K., Benvin, S. et al.,Structural requirements of double-stranded RNA for the activation of 2_,5_-oligo(A) polymerase and protein kinase of interferontreated HeLa cells. J. Biol. Chem., 254(20) (1979) 10180.

    CAS  PubMed  Google Scholar 

  76. Manche, L., Green, S.R., Schmedt, C. et al.,Interactions between double-stranded RNA regulators and the protein kinase DAI. Mol. Cell Biol., 12(11) (1992) 5238.

    CAS  PubMed  Google Scholar 

  77. Caplen, N.J., Parrish, S., Imani, F. et al.,Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems. Proc. Natl. Acad. Sci. USA, 98(17) (2001) 9742.

    Article  CAS  PubMed  Google Scholar 

  78. Elbashir, S.M., Harborth, J., Lendeckel, W. et al.,Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature, 411(6836) (2001) 494.

    Article  CAS  PubMed  Google Scholar 

  79. Billy, E., Brondani, V., Zhang, H. et al.,Specific interference with gene expression induced by long, double-stranded RNA in mouse embryonal teratocarcinoma cell lines. Proc. Natl. Acad. Sci. USA, 98(25) (2001) 14428.

    Article  CAS  PubMed  Google Scholar 

  80. Paddison, P.J., Caudy, A.A. and Hannon, G.J., Stable suppression of gene expression by RNAi in mammalian cells. Proc. Natl. Acad. Sci. USA, 99(3) (2002) 1443.

    Article  CAS  PubMed  Google Scholar 

  81. Hutvagner, G. and Zamore, P.D., A microRNA in a multipleturnover RNAi enzyme complex. Science, 297(5589) (2002) 2056.

    Article  CAS  PubMed  Google Scholar 

  82. Doi, N., Zenno, S., Ueda, R. et al.,Short-interfering-RNAmediated gene silencing in mammalian cells requires dicer and eIF2C translation initiation factors. Curr. Biol., 13(1) (2003) 41.

    Article  CAS  PubMed  Google Scholar 

  83. Elbashir, S.M., Harborth, J., Weber, K. et al.,Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods, 26 (2) (2002) 199.

    Google Scholar 

  84. Chiu, Y.L. and Rana, T.M., RNAi in human cells: Basic structural and functional features of small interfering RNA. Mol. Cell, 10(3) (2002) 549.

    CAS  PubMed  Google Scholar 

  85. Harborth, J., Elbashir, S.M., Vandenburgh, K. et al.,Sequence, chemical, and structural variation of small interfering RNAs and short hairpin RNAs and the effect on mammalian gene silencing. Antisense Nucl. Acids Drug Dev., 13(2) (2003) 83.

    CAS  Google Scholar 

  86. Holen, T., Amarzguioui, M., Wiiger, M.T. et al.,Positional effects of short interfering RNAs targeting the human coagulation trigger tissue factor. Nucl. Acids Res., 30(8) (2002) 1757.

    Article  CAS  PubMed  Google Scholar 

  87. Lee, N.S., Dohjima, T., Bauer, G., et al.,Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nat. Biotechnol., 20(5) (2002) 500.

    CAS  PubMed  Google Scholar 

  88. Semizarov, D., Frost, L., Sarthy, A. et al.,Specificity of short interfering RNA determined through gene expression signatures. Proc. Natl. Acad. Sci. USA, 100(11) (2003) 6347.

    Article  CAS  PubMed  Google Scholar 

  89. Jackson, A.L., Bartz, S.R., Schelter, J. et al.,Expression profiling reveals off-target gene regulation by RNAi. Nat. Biotechnol., 21(6) (2003) 635.

    Article  CAS  PubMed  Google Scholar 

  90. Doench, J.G., Petersen, C.P. and Sharp, P.A., siRNAs can function as miRNAs. Genes Dev., 17(4) (2003) 438.

    Article  CAS  PubMed  Google Scholar 

  91. Chi, J.T., Chang, H.Y., Wang, N.N. et al.,Genomewide view of gene silencing by small interfering RNAs. Proc. Natl. Acad. Sci. USA, 100(11) (2003) 6343.

    Article  CAS  PubMed  Google Scholar 

  92. Amarzguioui, M., Holen, T., Babaie, E. et al.,Tolerance for mutations and chemical modifications in a siRNA. Nucl. Acids Res, 31(2) (2003) 589.

    Article  CAS  PubMed  Google Scholar 

  93. Brummelkamp, T.R., Bernards, R. and Agami, R., A system for stable expression of short interfering RNAs in mammalian cells. Science, 296(5567) (2002) 550.

    Article  CAS  PubMed  Google Scholar 

  94. Brummelkamp, T.R., Bernards, R. and Agami, R., Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2(3) (2002) 243.

    Article  CAS  PubMed  Google Scholar 

  95. Miller, V.M., Xia, H., Marrs, G.L. et al.,Allele-specific silencing of dominant disease genes. Proc. Natl. Acad. Sci. USA, 100(12) (2003) 7195.

    Article  CAS  PubMed  Google Scholar 

  96. Kisielow, M., Kleiner, S., Nagasawa, M. et al.,Isoformspecific knockdown and expression of adaptor protein ShcA using small interfering RNA. Biochem. J., 363(Pt 1) (2002) 1.

    CAS  PubMed  Google Scholar 

  97. Stein, P., Svoboda, P. and Schultz, R.M., Transgenic RNAi in mouse oocytes: A simple and fast approach to study gene function. Dev. Biol., 256(1) (2003) 188.

    Article  Google Scholar 

  98. Tabara, H., Grishok, A. and Mello, C.C., RNAi in C.elegans: Soaking in the genome sequence. Science, 282(5388) (1998) 430.

    Article  CAS  PubMed  Google Scholar 

  99. Timmons, L. and Fire, A., Specific interference by ingested dsRNA. Nature, 395(6705) (1998) 854.

    Article  CAS  PubMed  Google Scholar 

  100. Kamath, R.S., Martinez-Campos, M., Zipperlen, P. et al., Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol., 2(1) (2000).

  101. Clemens, J.C., Worby, C.A., Simonson-Leff, N. et al.,Use of double-stranded RNA interference in drosophila cell lines to dissect signal transduction pathways. Proc. Natl. Acad. Sci. USA, 97(12) (2000) 6499.

    Article  CAS  PubMed  Google Scholar 

  102. Caplen, N.J., Fleenor, J., Fire, A. et al.,dsRNA-mediated gene silencing in cultured Drosophilacells: A tissue culture model for the analysis of RNA interference. Gene., 252(1–2) (2000) 95.

    CAS  PubMed  Google Scholar 

  103. Kennerdell, J.R. and Carthew, R.W., Heritable gene silencing in Drosophilausing double-stranded RNA. Nat. Biotechnol., 18(8) (2000) 896.

    CAS  PubMed  Google Scholar 

  104. Donze, O. and Picard, D., RNA interference in mammalian cells using siRNAs synthesized with T7 RNA polymerase. Nucl. Acids Res, 30(10) (2002) e46.

    Google Scholar 

  105. Yu, J.Y., DeRuiter, S.L. and Turner, D.L., RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells. Proc. Natl. Acad. Sci. USA, 99(9) (2002) 6047.

    Article  CAS  PubMed  Google Scholar 

  106. Calegari, F., Haubensak, W., Yang, D. et al.,Tissue-specific RNA interference in postimplantation mouse embryos with endoribonuclease-prepared short interfering RNA. Proc. Natl. Acad. Sci. USA, 99(22) (2002) 14236.

    Article  CAS  PubMed  Google Scholar 

  107. Yang, D., Buchholz, F., Huang, Z. et al.,Short RNA duplexes produced by hydrolysis with Escherichia coliRNase III mediate effective RNA interference in mammalian cells. Proc. Natl. Acad. Sci. USA, 99(15) (2002) 9942.

    Article  CAS  PubMed  Google Scholar 

  108. Myers, J.W., Jones, J.T., Meyer, T. et al.,Recombinant Dicer efficiently converts large dsRNAs into siRNAs suitable for gene silencing. Nat. Biotechnol., 21(3) (2003) 324.

    Article  CAS  PubMed  Google Scholar 

  109. Kawasaki, H., Suyama, E., Iyo, M. et al.,siRNAs generated by recombinant human Dicer induce specific and significant but target site-independent gene silencing in human cells. Nucl. Acids Res., 31(3) (2003) 981.

    Article  CAS  PubMed  Google Scholar 

  110. Paddison, P.J., Caudy, A.A., Bernstein, E. et al.,Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev., 16(8) (2002) 948.

    Article  CAS  PubMed  Google Scholar 

  111. Castanotto, D., Li, H. and Rossi, J.J., Functional siRNA expression from transfected PCR products. Rna, 8(11) (2002) 1454.

    Article  CAS  PubMed  Google Scholar 

  112. Miyagishi, M. and Taira, K., U6 promoter driven siRNAs with four uridine 3_ overhangs efficiently suppress targeted gene expression in mammalian cells. Nat. Biotechnol., 20(5) (2002) 497.

    Article  CAS  PubMed  Google Scholar 

  113. Sui, G., Soohoo, C., Affar el, B. et al.,A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc. Natl. Acad. Sci. USA, 99(8) (2002) 5515.

    Article  CAS  PubMed  Google Scholar 

  114. Paul, C.P., Good, P.D., Winer, I. et al.,Effective expression of small interfering RNA in human cells. Nat. Biotechnol., 20(5) (2002) 505.

    Article  CAS  PubMed  Google Scholar 

  115. Kawasaki, H. and Taira, K., Short hairpin type of dsRNAs that are controlled by tRNA(Val) promoter significantly induce RNAi-mediated gene silencing in the cytoplasm of human cells. Nucl. Acids Res, 31(2) (2003) 700.

    Article  CAS  PubMed  Google Scholar 

  116. Paul, C.P., Good, P.D., Li, S.X. et al.,localized expression of small RNA inhibitors in human cells. Mol. Ther., 7(2) (2003) 237.

    Article  CAS  PubMed  Google Scholar 

  117. Barton, G.M. and Medzhitov, R., Retroviral delivery of small interfering RNA into primary cells. Proc. Natl. Acad. Sci. USA, 99(23) (2002) 14943.

    Article  CAS  PubMed  Google Scholar 

  118. Devroe, E. and Silver, P.A., Retrovirus-delivered siRNA. BMC Biotechnol., 2(1) (2002) 15.

    Article  PubMed  Google Scholar 

  119. Xia, H., Mao, Q., Paulson, H.L. et al.,siRNA-mediated gene silencing in vitroand in vivo. Nat. Biotechnol., 20(10) (2002) 1006.

    Article  CAS  PubMed  Google Scholar 

  120. McManus, M.T., Petersen, C.P., Haines, B.B. et al.,Gene silencing using micro-RNA designed hairpins. Rna 8(6) (2002) 842.

    Article  CAS  PubMed  Google Scholar 

  121. Bridge, A.J., Pebernard, S., Ducraux, A. et al.,Induction of an interferon response by RNAi vectors in mammalian cells. Nat. Genet. (2003).

  122. Fraser, A.G., Kamath, R.S., Zipperlen, P. et al.,Functional genomic analysis of C.eleganschromosome I by systematic RNA interference. Nature, 408(6810) (2000) 325.

    CAS  PubMed  Google Scholar 

  123. Gonczy, P., Echeverri, G., Oegema, K. et al.,Functional genomic analysis of cell division in C.elegansusing RNAi of genes on chromosome III. Nature, 408(6810) (2000) 331.

    CAS  PubMed  Google Scholar 

  124. Piano, F., Schetterdagger, A.J., Mangone, M. et al.,RNAi analysis of genes expressed in the ovary of Caenorhabditis elegans. Curr. Biol., 10(24) (2000) 1619.

    Article  CAS  PubMed  Google Scholar 

  125. Piano, F. Schetter, A.J., Morton, D.G. et al.,Gene clustering based on RNAi phenotypes of ovary-enriched genes in C. elegans. Curr. Biol., 12(22) (2002) 1959.

    Article  CAS  PubMed  Google Scholar 

  126. Lee, S.S., Lee, R.Y., Fraser, A.G. et al.,A systematic RNAi screen identifies a critical role for mitochondria in C.eleganslongevity. Nat. Genet., 33(1) (2003) 40.

    Article  CAS  PubMed  Google Scholar 

  127. Kamath, R.S., Fraser, A.G., Dong, Y. et al.,Systematic functional analysis of the Caenorhabditis elegansgenome using RNAi. Nature, 421(6920) (2003) 231.

    Article  CAS  PubMed  Google Scholar 

  128. Ashrafi, K., Chang, F.Y., Watts, J.L. et al.,Genomewide RNAi analysis of Caenorhabditis elegansfat regulatory genes. Nature, 421(6920) (2003) 268.

    Article  CAS  PubMed  Google Scholar 

  129. Pothof, J., Van Haaften, G., Thijssen, K. et al.,Identification of genes that protect the C.elegansgenome against mutations by genome-wide RNAi. Genes Dev., 17(4) (2003) 443.

    Article  CAS  PubMed  Google Scholar 

  130. Lum, L., Yao, S., Mozer, B. et al.,Identification of Hedgehog pathway components by RNAi in Drosophilacultured cells. Science, 299(5615) (2003) 2039.

    Article  CAS  PubMed  Google Scholar 

  131. Vickers, T.A., Koo, S., Bennett, C.F. et al.,Efficient reduction of target RNAs by small interfering RNA and RNase H-dependent antisense agents. A comparative analysis. J.Biol. Chem., 278(9) (2003) 7108.

    Article  CAS  PubMed  Google Scholar 

  132. Aoki, Y., Cioca, D., Oidaira, H. et al.,RNA interference may be more potent than antisense RNA in human cancer cell lines. Clin. Exp. Pharmacol. Physiol., 30(1–2) (2003) 96.

    CAS  PubMed  Google Scholar 

  133. Miyagishi, M., Hayashi, M. and Taira, K., Comparison of the suppressive effects of antisense oligonucleotides and siRNAs directed against the same targets in mammalian cells. Antisense Nucl. Acids Drug Dev., 13(1) (2003) 1.

    CAS  Google Scholar 

  134. Stucke, V.M., Sillje, H.H., Arnaud, L. et al.,Human Mps1 kinase is required for the spindle assembly checkpoint but not for centrosome duplication. Embo J., 21(7) (2002) 1723.

    Article  CAS  PubMed  Google Scholar 

  135. Mailand, N., Lukas, C., Kaiser, B.K. et al.,Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation. Nat. Cell Biol., 4(4) (2002) 318.

    Article  Google Scholar 

  136. Harborth, J., Elbashir, S.M., Bechert, K. et al.,Identification of essential genes in cultured mammalian cells using small interfering RNAs. J. Cell Sci., 114(Pt 24) (2001) 4557.

    CAS  PubMed  Google Scholar 

  137. Hasuwa, H., Kaseda, K., Einarsdottir, T. et al.,Small interfering RNA and gene silencing in transgenic mice and rats. FEBS Lett., 532(1–2) (2002) 227.

    CAS  PubMed  Google Scholar 

  138. Tiscornia, G., Singer, O., Ikawa, M. et al.,A general method for gene knockdown in mice by using lentiviral vectors expressing small interfering RNA. Proc. Natl. Acad. Sci. USA, 100(4) (2003) 1844.

    Article  CAS  PubMed  Google Scholar 

  139. Carmell, M.A., Zhang, L., Conklin, D.S. et al.,Germline transmission of RNAi in mice. Nat. Struct. Biol.,2003.

  140. Rubinson, D.A., Dillon, C.P., Kwiatkowski, A.V. et al., Corrigendum: A lentivirus-based system to silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat. Genet., 34(2) (2003) 231.

    CAS  Google Scholar 

  141. Kunath, T., Gish, G., Lickert, H. et al.,Transgenic RNA interference in ES cell-derived embryos recapitulates a genetic null phenotype. Nat. Biotechnol., 21(5) (2003) 559.

    Article  CAS  PubMed  Google Scholar 

  142. Hemann, M.T., Fridman, J.S., Zilfou, J.T. et al.,An epiallelic series of p53 hypomorphs created by stable RNAi produced distinct tumor phenotypes in vivo. Nat. Genet., 2003; 3 February 2003, doi:10.1038/ng1091.

  143. Paddison, P.J. and Hannon, G.J., RNA interference: The new somatic cell genetics? Cancer Cell 2(1) (2002) 17.

    Article  CAS  PubMed  Google Scholar 

  144. Frankish, H., Consortium uses RNAi to uncover genes' function. Lancet, 361(9357) (2003) 584.

    Article  PubMed  Google Scholar 

  145. McCaffrey, A.P., Meuse, L., Pham, T.T. et al.,RNA interference in adult mice. Nature, 418(6893) (2002) 38–9.

    Article  Google Scholar 

  146. Lewis, D.L., Hagstrom, J.E., Loomis, A.G. et al.,Effi-cient delivery of siRNA for inhibition of gene expression in postnatal mice. Nat. Genet., 32(1) (2002) 107.

    Article  CAS  PubMed  Google Scholar 

  147. Zender, L., Hutker, S., Liedtke, C., et al.,Caspase 8 small interfering RNA prevents acute liver failure in mice. Proc. Natl. Acad. Sci. USA, (2003).

  148. Wilda, M., Fuchs, U., Wossmann, W. et al.,Killing of leukemic cells with a BCR/ABL fusion gene by RNA interference (RNAi). Oncogene, 21(37) (2002) 5716.

    Article  CAS  PubMed  Google Scholar 

  149. Scherr, M., Battmer, K., Winkler, T. et al.,Specific inhibition of bcr-abl gene expression by small interfering RNA. Blood, 101(4) (2003) 1566.

    Article  CAS  PubMed  Google Scholar 

  150. Zhang, L., Yang, N., Mohamed-Hadley, A. et al.,Vectorbased RNAi, a novel tool for isoform-specific knock-down of VEGF and anti-angiogenesis gene therapy of cancer. Biochem. Biophys. Res Commun., 303(4) (2003) 1169.

    Article  CAS  PubMed  Google Scholar 

  151. Nagy, P., Arndt-Jovin, D.J. and Jovin, T.M., Small interfering RNAs suppress the expression of endogenous and GFP-fused epidermal growth factor receptor (erbB1) and induce apoptosis in erbB1-overexpressing cells. Exp. Cell Res, 285(1) (2003) 39.

    Article  CAS  PubMed  Google Scholar 

  152. Wu, H., Hait, W.N. and Yang, J.M., Small interfering RNA-induced suppression of MDR1 (P-glycoprotein) restores sensitivity to multidrug-resistant cancer cells. Cancer Res, 63(7) (2003) 1515.

    CAS  PubMed  Google Scholar 

  153. Novina, C.D., Murray, M.F., Dykxhoorn, D.M. et al.,siRNAdirected inhibition of HIV-1 infection. Nat. Med., 8(7) (2002) 681.

    CAS  PubMed  Google Scholar 

  154. Martinez, M.A., Gutierrez, A., Armand-Ugon, M. et al., Suppression of chemokine receptor expression by RNA interference allows for inhibition of HIV-1 replication. Aids, 16(18) (2002) 2385.

    Article  CAS  PubMed  Google Scholar 

  155. Qin, X.F., An, D.S., Chen, I.S. et al.,Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Proc. Natl. Acad. Sci. USA, 100(1) (2003) 183.

    Article  CAS  PubMed  Google Scholar 

  156. Song, E., Lee, S.K., Dykxhoorn, D.M. et al.,Sustained small interfering RNA-mediated human immunodeficiency virus type 1 inhibition in primary macrophages. J. Virol., 77(13) (2003) 7174.

    Article  CAS  PubMed  Google Scholar 

  157. Capodici, J., Kariko, K. and Weissman, D., Inhibition of HIV-1 infection by small interfering RNA-mediated RNA interference. J. Immunol., 169(9) (2002) 5196.

    PubMed  Google Scholar 

  158. Park, W.S., Miyano-Kurosaki, N., Hayafune, M. et al., Prevention of HIV-1 infection in human peripheral blood mononuclear cells by specific RNA interference. Nucl. Acids Res., 30(22) (2002) 4830.

    Article  CAS  PubMed  Google Scholar 

  159. Coburn, G.A. and Cullen, B.R., Potent and specific inhibition of human immunodeficiency virus type 1 replication by RNA interference. J. Virol., 76(18) (2002) 9225.

    Article  CAS  PubMed  Google Scholar 

  160. Jacque, J.M., Triques, K. and Stevenson, M., Modulation of HIV-1 replication by RNA interference. Nature, 418(6896) (2002) 435.

    Article  CAS  PubMed  Google Scholar 

  161. Kapadia, S.B., Brideau-Andersen, A. and Chisari, F.V., Interference of hepatitis C virus RNA replication by short interfering RNAs. Proc. Natl. Acad. Sci. USA, 100(4) (2003) 2014.

    Article  CAS  PubMed  Google Scholar 

  162. Randall, G., Grakoui, A. and Rice, C.M., Clearance of replicating hepatitis C virus replicon RNAs in cell culture by small interfering RNAs. Proc. Natl. Acad. Sci. USA, 100(1) (2003) 235.

    Article  CAS  PubMed  Google Scholar 

  163. Wilson, J.A., Jayasena, S., Khvorova, A. et al.,RNA interference blocks gene expression and RNA synthesis from hepatitis C replicons propagated in human liver cells. Proc. Natl. Acad. Sci. USA, 100(5) (2003) 2783.

    Article  CAS  PubMed  Google Scholar 

  164. Seo, M.Y., Abrignani, S., Houghton, M. et al.,Small interfering RNA-mediated inhibition of hepatitis C virus replication in the human hepatoma cell line Huh-7. J. Virol., 77(1) (2003) 810.

    CAS  PubMed  Google Scholar 

  165. Gitlin, L., Karelsky, S. and Andino, R., Short interfering RNA confers intracellular antiviral immunity in human cells. Nature, 418(6896) (2002) 430.

    Article  CAS  PubMed  Google Scholar 

  166. Bitko, V. and Barik, S., Phenotypic silencing of cytoplasmic genes using sequence-specific double-stranded short interfering RNA and its application in the reverse genetics of wild type negative-strand RNA viruses. BMC Microbiol., 1(1) (2001) 34.

    Article  CAS  PubMed  Google Scholar 

  167. Ge, Q., McManus, M.T., Nguyen, T. et al.,RNA interference of influenza virus production by directly targeting mRNA for degradation and indirectly inhibiting all viral RNA transcription. Proc. Natl. Acad. Sci. USA, 100(5) (2003) 2718.

    Article  CAS  PubMed  Google Scholar 

  168. Jia, Q. and Sun, R., Inhibition of gammaherpesvirus replication by RNA interference. J. Virol., 77(5) (2003) 3301.

    Article  CAS  PubMed  Google Scholar 

  169. Jiang, M. and Milner, J., Selective silencing of viral gene expression in HPV-positive human cervical carcinoma cells treated with siRNA, a primer of RNA interference. Oncogene, 21(39) (2002) 6041.

    CAS  PubMed  Google Scholar 

  170. Caplen, N.J., Taylor, J.P., Statham, V.S. et al.,Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference. Hum. Mol. Genet., 11(2) (2002) 175.

    Article  CAS  PubMed  Google Scholar 

  171. Gonzalez-Alegre, P., Miller, V.M., Davidson, B.L. et al.,Toward therapy for DYT1 dystonia: Allele-specific silencing of mutant TorsinA. Ann. Neurol., 53(6) (2003) 781.

    Article  CAS  PubMed  Google Scholar 

  172. Song, E., Lee, S.K., Wang, J. et al.,RNA interference targeting Fas protects mice from fulminant hepatitis. Nat. Med., 9(3) (2003) 347.

    Article  CAS  PubMed  Google Scholar 

  173. Mousses, S., Caplan, N.J., Cornelisen, R. et al.,RNAi microarray analysis in cultured mammalian cells. Genome Research 13 (2003) 2341.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Translational Genomics Research Institute (TGen), 20 Firstfield Road, Suite 110, Gaithersburg, MD, 20878, U.S.A

    David O. Azorsa & Spyro Mousses

  2. Medical Genetics Branch, National Human Genome Research Institute National Institutes of Health, Building 10, Room 10C103, 10 Center Drive, Bethesda, MD, 20892, U.S.A.

    Natasha J. Caplen

  3. National Cancer Institute, National Institutes of Health, Building 37, Room 3128B, 37 Convent Drive, Bethesda, MD, 20892, U.S.A

    Natasha J. Caplen

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Azorsa, D.O., Mousses, S. & Caplen, N.J. Gene silencing through RNA interference: Potential for therapeutics and functional genomics. Int J Pept Res Ther 10, 361–372 (2003). https://doi.org/10.1007/s10989-004-4900-3

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